3-Trifluoroacetyl amino-1-aryl-2-pyrazolines

ABSTRACT

This disclosure describes novel 3-substituted amino-1-phenyl-2-pyrazolines and 3-substituted amino-1-mono and disubstituted phenyl-2-pyrazolines and their C 4  and C 5  analogs, effective as anti-inflammatory and analgesic agents, and as antibacterial agents and/or antifungal agents.

PRIOR ART

1. R. Battisti, et. al., U.S. Pat. No. 4,149,005 (Apr. 10, 1979)discloses compounds of the formula: ##STR1## where R is H or CH₃, X isH, Br, Cl, alkyl, alkoxy or carboxyalkyl groups with from 1 to 4 carbonatoms or CF₃ ; and n is 1 or 2. These are disclosed as being used asintermediates in the preparation of 1-phenyl-3-aminopyrazoles ascoupling components in azo dye manufacture. Related foreign patents:Ger. Offen. No. 2,727,706; French No. 2,355,834; Gr. Br. No. 1,515,500;Belgium No. 855,944; Netherland No. 7,706,760 and Japan No. 28,168.

2. G. A. Higgs, et. al., (Wellcome Research Laboratories); BiochemicalPharmacology, 28, 1959 (1979) discloses3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C); ##STR2##This compound is reported to have anti-inflammatory activity.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and more particularly isconcerned with novel 3-substituted amino-1-phenyl-2-pyrazolines and3-substituted amino-1-mono and disubstituted phenyl-2-pyrazolines andtheir C₄ and C₅ analogs which may be represented by the followinggeneral formulae: ##STR3## wherein R₁ is hydrogen and lower alkyl (C₁-C₄); R₂ is hydrogen, lower alkyl (C₁ -C₄), phenyl and ##STR4## where R₅is halogen; R₃ is ##STR5## where R₆ and R₇ may be hydrogen, chloro,fluoro, lower alkyl (C₁ -C₄), trifluoromethyl and COCF₃ ; R₄ is --CHO,--COCF₃ and --COR₈ where R₈ is lower alkyl (C₁ -C₄) and thepharmacologically acceptable acid-addition salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are generally obtainable aswhite to pale yellow crystalline solids having characteristic meltingpoints and absorption spectra. The bases are appreciably soluble insolvents such as acetone, ethanol, toluene, methylene chloride and thelike but are relatively insoluble in water. The organic bases of thepresent invention form non-toxic acid-addition salts with a variety ofpharmacologically acceptable organic and inorganic salt formingreagents. Thus, acid-addition salts, formed by admixture of the organicfree base with one or two equivalents of an acid, suitably in a neutralsolvent, are formed with such acids as sulfuric, phosphoric,hydrochloric, hydriodic, sulfamic, citric, lactic, fumaric, succinic,tartaric, acetic, benzoic, gluconic, ascorbic, and the like. Theacid-addition salts are relatively insoluble in non-polar organicsolvents such as diethyl ether, benzene, toluene, and the like but areappreciably soluble in water. For purposes of this invention, the freebases are equivalent to their non-toxic acid-addition salts.

Preparation of the novel 3-substituted amino-1-heteroaryl-2-pyrazolinesIV of the instant invention, which are active as antibacterial and/orantifungal agents is accomplished by the adaptation of the procedure ofDuffin, G. F. and Kendall, J. D., J. Chem. Soc., 1954, 408; inaccordance with the following reaction scheme: ##STR6## wherein R₁, R₂,R₃ and R₄ are as previously defined.

In accordance with the above reaction scheme, an arylhydrazine or ahalogen-mono or disubstituted arylhydrazine or salt thereof II such asphenylhydrazine, m-chlorophenylhydrazine hydrochloride,p-chlorophenylhydrazine hydrochloride, m- and p-fluorophenylhydrazinehydrochloride, m-tolylhydrazine hydrochloride,m-trifluoromethylphenylhydrazine hydrochloride and3,4-dichlorophenylhydrazine hydrochloride is reacted with anα,β-unsaturated nitrile I, such as acrylonitrile, methacrylonitrile,crotononitrile, cinnamonitrile, p-chlorocinnamonitrile,4-methylcinnamonitrile, butyl acrylonitrile or a compound such asβ-ethoxypropionitrile (which can undergo base catalyzed elimination toyield I) in a base catalyzed condensation procedure, with a base such assodium ethoxide or choline hydrate in absolute ethanol. The reactionmixture is refluxed for a period of from 2-20 hours, then the solvent isremoved in vacuo. Water addition gives a filterable solid which iscollected, dissolved in dichloromethane and passed through a shortcolumn of a hydrous magnesium silicate. The effluent is then refluxedwith the gradual addition of solvent such as hexane untilcrystallization is noted.

Recrystallization from the same solvent pair (with or without additionaltreatment with a hydrous magnesium silicate) or from acetone-hexaneprovides the 3-amino-1-aryl-2-pyrazoline and 3-amino-1-mono anddisubstituted phenyl-2-pyrazoline compounds III. If the pyrazoline IIIis not soluble in dichloromethane, recrystallization may be accomplishedfrom acetone-hexane, 95% ethanol or benzene with the omission of thehydrous magnesium silicate treatment phase.

The pyrazoline compound III is then subjected to N-acylation by treatingwith an acylating agent such as a mixture of formic acid and aceticanhydride (Feiser and Feiser, Reagents for Organic Synthesis, Vol. 1,page 4), acetic anhydride or propionic anhydride (with or without acatalyst such as 4-dimethylamino pyridine) or with trifluoroaceticanhydride at room temperature for 2-48 hours to yield the correspondingnovel products of the invention IV which for the most part may berecrystallized from dichloromethane-hexane.

The compounds of the present invention have utility as pharmacologicalagents. They have active agents that ameliorate inflammation, asanalgesic agents and as antibacterial and/or antifungal agents and inmany cases are active in more than one of these areas.

Representative compounds of this invention have been proven to be activein vivo as anti-inflammatory agents when tested by the CarrageeninInduced Edema of the Rat Paw Test. This test is a modification of themethod of Winter, C. A., et al., Proc. Soc. Exp. Biol. and Med., 111,544 (1962). Compounds found to be active in this test are:

2,2,2-Trifluoro-N-(4-methyl-1-phenyl-2-pyrazolin-3-yl)acetamide

N-[1-(3,4-Dichlorophenyl)-3-pyrazolin-3-yl]formamide

N-[1-(p-Chlorophenyl)-5-methyl-2-pyrazolin-3-yl]formamide

N-[1-(p-Fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

N-(1-Phenyl-2-pyrazolin-3-yl)propionamide

2,2,2-Trifluoro-N-(1-phenyl-2-pyrazolin-3-yl)acetamide

2,2,2-Trifluoro-N-[1-(p-fluorophenyl)-2-pyrazolin-3-yl]acetamide

N-[1-(p-Fluorophenyl)-5-methyl-2-pyrazolin-3-yl]propionamide

Another in vivo method of determining drug effect on conditions whichresult in the production of pain is measuring the effect on ultravioletinduced erythema in guinea pigs [Winder, C. V., et al., A Study ofPharmacological Influences on Ultraviolet Erythema in Guinea Pigs, Arch.Int. Pharmacodyn., 116, 261 (1958)]. A representative compound of thepresent invention which is active when tested by the ultraviolet inducederythema test isN-[1-(p-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide.

A test used to show activity against chronic inflammation in adjuvantarthritis is a modification of the technique of Newbald, B.,"Chemotherapy of Arthritis Induced In Rats by Mycobacterial Adjuvant",Brit. J. Pharmacol. Chemother., 21, 127 (1963), which is described inU.S. Pat. No. 3,863,010. Representative compounds of the presentinvention found to be active when tested by the Adjuvant Arthritis Testare:

N-[1-(p-Chlorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

2,2,2-Trifluoro-N-[1-(p-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

The compounds of the present invention also possess activity asanalgesic agents. A method employed for measuring the in vivo activityof the compounds of the present invention is the "writhing syndrome"test for analgesic activity as described by Siegmund, et al.,Proceedings of the Society for Experimental Biology and Medicine, 95,729 (1957), with modification as described in U.S. Pat. No. 3,863,010.Representative compounds of the present invention which are active whentested by the "writhing syndrome" test are listed as follows:

2,2,2-Trifluoro-N-[5-methyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide

2,2,2-Trifluoro-N-(4-methyl-1-phenyl-2-pyrazolin-3-yl)acetamide

N-(1,5-Diphenyl-2-pyrazolin-3-yl)-2,2,2-trifluoroacetamide

N-[1,5-Bis(p-chlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

N-(5-Methyl-1-phenyl-2-pyrazolin-3-yl)acetamide

N-[1-(p-Fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

N-(1-Phenyl-2-pyrazolin-3-yl)propionamide

N-(1-m-Tolyl-2-pyrazolin-3-yl)acetamide

2,2,2-Trifluoro-N-[4-methyl-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazolin-3-yl]acetamide

2,2,2-Trifluoro-N-[1-(p-fluorophenyl)-5-phenyl-2-pyrazolin-3-yl]acetamide

2,2,2-Trifluoro-N-[1-(p-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

N-[1-(p-Fluorophenyl)-5-methyl-2-pyrazolin-3-yl]propionamide

N-[1-(p-Fluorophenyl)-4-methyl-2-pyrazolin-3-yl]formamide

N-[5-(p-Chlorophenyl)-1-(m-fluorophenyl)-2-pyrazolin-3-yl]formamide

Representative compounds of the present invention have been provenactive in vitro as antibacterial and/or antifungal agents when tested bysuch procedures as the standard agar dilution procedure. Compoundsproven active in this test include:

N-[1-(3,4-Dihclorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

2,2,2-Trifluoro-N-[5-methyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide

2,2,2-Trifluoro-N-(4-methyl-1-phenyl-2-pyrazolin-3-yl)acetamide

2,2,2Trifluoro-N-[4-methyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide

N-(1,5-Diphenyl-2-pyrazolin-3-yl)-2,2,2-trifluoroacetamide

N-[1-(m-Chlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

N-[1,5-Bis(p-chlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

N-[1-(3,4-Dichlorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

N-[1-(3,4-Dichlorophenyl)-4-methyl-2-pyrazolin-3-yl]formamide

N-[1-(3,4-Dichlorophenyl)-2-pyrazolin-3-yl]formamide

N-(1-Phenyl-2-pyrazolin-3-yl)acetamide

N-[1-(m-Chlorphenyl)-2-pyrazolin-3-yl]formamide

N-[1-(p-Chlorophenyl)-5-methyl-2-pyrazolin-3-yl]formamide

N-[1-(p-Chlorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

N-(1-Phenyl-2-pyrazolin-3-yl)formamide

N-[1-(m-Chlorophenyl)-4-methyl-2-pyrazolin-3-yl]formamide

N-(5-Methyl-1-phenyl-2-pyrazolin-3-yl)acetamide

N-[1-(p-Fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

N-[5-(p-Chlorophenyl)-1-(m-fluorophenyl)-2-pyrazolin-3-yl]acetamide

N-[5-(p-Chlorophenyl)-1-(p-fluorophenyl)-2-pyrazolin-3-yl]acetamide

N-[1-(p-Chlorophenyl)-4-methyl-2-pyrazolin-3-yl]acetamide

N-(1-Phenyl-2-pyrazolin-3-yl)propionamide

N-[1-(m-Fluorophenyl)-4-methyl-2-pyrazolin-3-yl]acetamide

N-(1-m-Tolyl-2-pyrazolin-3-yl)acetamide

2,2,2-Trifluoro-N-(1-phenyl-2-pyrazolin-3-yl)acetamide

N-(1,5-Diphenyl-2-pyrazolin-3-yl)formamide

2,2,2-Trifluoro-N-[1-(p-fluorophenyl)-2-pyrazolin-3-yl]acetamide

2,2,2-Trifluoro-N-[1-(4-trifluoroacetyl-m-tolyl)-2-pyrazolin-3-yl]acetamide

2,2,2-Trifluoro-N-[1-(p-fluorophenyl)-5-phenyl-2-pyrazolin-3-yl]acetamide

2,2,2-Trifluoro-N-[1-(p-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

N-[1-(p-Fluoropheny)-5-methyl-2-pyrazolin-3-yl]propionamide

N-[1-(p-Fluorophenyl)-4-methyl-2-pyrazolin-3-yl]formamide

N-(5-Methyl-1-phenyl-2-pyrazolin-3-yl)propionamide

N-[1-(p-Fluorophenyl)-5-phenyl-2-pyrazolin-3-yl]formamide

N-[5-(p-Chlorophenyl)-1-(m-fluorophenyl)-2-pyrazolin-3-yl]formamide

N-[5-(p-Chlorophenyl)-1-phenyl-2-pyrazolin-3-yl]formamide

N-[1-(p-Chlorophenyl)-5-phenyl-2-pyrazolin-3-yl]formamide

N-[1,5-Bis-(p-chlorophenyl)-2-pyrazolin-3-yl]formamide

The compounds of the present invention have been found to be highlyuseful for meliorating inflammation and as analgetic agents and asantibacterial and/or antifungal agents in treating mammals whenadministered in amounts ranging from about one milligram to about 250mg. per kilogram of body weight per day. A preferred dosage regimen foroptimum results would be from about 5 mg. to about 100 mg. per kilogramof body weight per day, and such dosage units are employed that a totalof from about 0.35 gram to about 7.0 grams of the active ingredient fora subject of about 70 kg. of body weight are administered in a 24 hourperiod. This dosage regimen may be adjusted to provide the optimumtherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A decidedpractical advantage of this invention is that the active ingredient maybe administered in any convenient manner such as by the oral,intravenous, intramuscular, intra-articular, topical or subcutaneousroutes.

Compositions according to the present invention having the desiredclarity, stability and adaptability for parenteral use are obtained bydissolving from 0.10% to 10.0% by weight of active compound in a vehicleconsisting of a polyhydric aliphatic alcohol or mixtures thereof.Especially satisfactory are glycerin, propylene glycol, and polyethyleneglycols. The polyethylene glycols consist of a mixture of non-volatile,normally liquid, polyethylene glycols which are soluble in both waterand organic liquids and which have molecular weights of from about 200to 1500. Although the amount of active compound dissolved in the abovevehicle may vary from 0.10 to 10.0% by weight, it is preferred that theamount of active compound employed be from about 3.0 to about 9.0% byweight. Although various mixtures of the aforementioned non-volatilepolyethylene glycols may be employed, it is preferred to use a mixturehaving an average molecular weight of from about 200 to about 400.

In addition to the active compound, the parenteral solutions may alsocontain various preservatives which may be used to prevent bacterial andfungal contamination. The preservatives which may be used for thesepurposes are, for example, myristyl-gamma-picolinium chloride, phenylmercuric nitrate, benzalkonium chloride, phenethyl alcohol,p-chlorophenyl-α-glycerol ether, methyl and propyl parabens, andthimerosal. As a practical matter it is also convenient to employantioxidants. Suitable antioxidants include, for example sodiumbisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate.Generally, from about 0.05 to about 0.2% concentrations of antioxidantare employed.

For intramuscular injection, the preferred concentration of activecompound is 0.25 to 0.50 mg./ml. of the finished compositions. Thecompounds of this invention are equally adapted to intravenousadministration when diluted with water or diluents employed inintravenous therapy such as isotonic glucose in appropriate quantities.For intravenous use, initial concentrations down to about 0.05 to 0.25mg./ml. of active compound are satisfactory.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds may be incorporated with excipientsand used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2% to about 60% of theweight of the unit. The amount of active ingredient in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 50 and 250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin: excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and flavoring such as cherry ororange flavor. Of course, any material used in preparing any dosage unitform should be pharmaceutically pure and substantially non-toxic in theamounts employed.

This invention will be described in greater detail in conjunction withthe following examples.

EXAMPLE 1N-[1-(3,4-Dichlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

A 9.9 g. amount of sodium metal is dissolved in 450 ml. of absoluteethanol, then 75.0 g. of 3,4-dichlorophenylhydrazine hydrochloride isadded followed in 10 minutes by 19.5 g. of acrylonitrile. The reactionmixture is refluxed for 18 hours. The solvent is removed in vacuo. Wateris added to separate a granular solid. The solid is dissolved in acetoneand filtered to remove a small amount of insoluble material. Thefiltrate is evaporated to dryness leaving a solid. The solid istriturated with ether to give 62.4 g. of3-amino-1-(3,4-dichlorophenyl)-2-pyrazoline as a tan crystalline solid,m.p. 181°-183° C.

A 10.0 g. amount of the preceding product is added portionwise withcooling and stirring to 50 ml. of trifluoroacetic anhydride withseparation of a solid. The reaction mixture is stirred for 3 hours atroom temperature then the solid is collected by filtration and dried togive 12.2 g. of product. A 3.0 g. amount of this material isrecrystallized from dichloromethane-hexane to give 2.4 g. of the productof the Example as pale yellow needles, m.p. 163°-164° C.

EXAMPLE 2 p-Chloro-N-[1-(3,4-dichlorophenyl)-2-pyrazolin-3-yl]benzamide

A stirred mixture of 2.30 g. of3-amino-1-(3,4-dichlorophenyl)-2-pyrazoline (prepared as described inExample 1) in 20 ml. of dry pyridine is cooled in an ice bath, then 2.10g. of p-chlorobenzoyl chloride is added. The reaction mixture is allowedto stand at room temperature for 16 hours then is poured into water toseparate a solid. The solid is collected by filtration and dissolved indichloromethane. This solution is passed through a short column of ahydrous magnesium silicate. The effluent is refluxed and hexane is addeduntil turbidity results. The solution is cooled and filtered to collecta product. The product is recrystallized from the same solvent pair togive 1.8 g. of the desired product as yellow needles, m.p. 177°-178° C.

EXAMPLE 32,2,2-Trifluoro-N-[5-p-tolyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide

A 1.0 g. amount of sodium metal is dissolved in 100 ml. of absoluteethanol, then 20.0 ml. of phenylhydrazine is added followed in 5 minutesby 24.0 ml. of (mixed cis and trans) 4-methylcinnamonitrile. Thereaction mixture is refluxed for 4 hours then is cooled. The precipitateis collected by filtration then is recrystallized from acetone-hexaneafter treatment with activated charcoal to give 14.25 g. of3-amino-1-phenyl-5-p-tolyl-2-pyrazoline as pale orange needles, m.p.165°-166° C.

A mixture of 5.0 g. of the preceding product and 25 ml. oftrifluoroacetic anhydride is allowed to stand at room temperature for 5minutes. The mixture is filtered and the solid collected is dissolved indichloromethane, then the solution is evaporated to dryness. The residueis again dissolved in dichloromethane and is passed through a hydrousmagnesium silicate and recrystallized as described in Example 2 to give1.5 g. of the product of the Example as matted pale yellow needles, m.p.206°-207° C.

EXAMPLE 42,2,2-Trifluoro-N-[5-phenyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide

A 2.0 g. amount of sodium metal is dissolved in 150 ml. of absoluteethanol, then 40.0 ml. of phenylhydrazine is added followed in 5 minutesby 48.0 ml. of cinnamonitrile. The reaction mixture is refluxed for 3hours with exothermic crystallization of a product. The product iscollected by filtration and washed with water. The material isrecrystallized from absolute ethanol to give 56.0 g. of3-amino-1,5-diphenyl-2-pyrazoline as a solid, m.p. 195°-197° C.

A mixture of 5.0 g. of the above product and 25.0 ml. of trifluoroaceticanhydride is allowed to stand at room temperature for 16 hours. Thesolvent is removed in vacuo and the residue is taken up indichloromethane. The solution is passed through a short column of ahydrous magnesium silicate and the product is recrystallized from theeffluent as described in Example 2. The entire recrystallizationprocedure is repeated to give 3.0 g. of the desired product as yellowneedles, m.p. 197°-198° C.

EXAMPLE 52,2,2-Trifluoro-N-[5-methyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetaide

(A) A 2.0 g. amount of sodium metal is dissolved in 200 ml. of absoluteethanol, then 32.4 g. of phenylhydrazine in 50 ml. of ethanol is added,followed in 10 minutes by 20.1 g. of crotononitrile. The reactionmixture is refluxed for 5 hours. Most of the ethanol is removed invacuo, water is added and the product is collected by filtration. Thesolid is dissolved in dichloromethane. This solution is passed through ashort column of a hydrous magnesium silicate. The column effluent isthen refluxed on a steam bath with the gradual addition of hexane tocrystallize a product. The product is collected and recrystallized fromacetone-hexane to give 26.9 g. of 3-amino-5-methyl-1-phenyl-2-pyrazolineas colorless prisms, m.p. 103.5°-106° C.

(B) A mixture of 5.0 g. of the preceding compound and 25.0 ml. oftrifluoroacetic anhydride is allowed to stand at room temperature for 48hours. Dichloromethane is added to dissolve the residual sludge. Thesolution is evaporated to dryness in vacuo. The residue is dissolved indichloromethane. The solution is passed through a short column of ahydrous magnesium silicate. Hexane is added to the effluent to separatea green oily precipitate. The solvent is decanted and evaporated to givea solid. The solid is again dissolved in dichloromethane, column treatedas above and recrystallized by the addition of hexane. The product iscollected by filtration and the above procedure is repeated to give 1.15g. of the product of the Example as yellow matted needles, m.p.189°-190.5° C.

EXAMPLE 62,2,2-Trifluoro-N-(4-methyl-1-phenyl-2-pyrazolin-3-yl)acetamide

A 2.0 g. amount of sodium metal is dissolved in 200 ml. of absoluteethanol, then 37.4 g. of phenylhydrazine is added followed in 10 minutesby 20.1 g. of methacrylonitrile. The reaction mixture is refluxed for 4hours then is evaporated to near dryness in vacuo. Water is added to theresidue to separate an oil. The oil is crystallized on standing. Thesolid is dissolved in dichloromethane and the solution is passed througha short column of a hydrous magnesium silicate. The column effluent isevaporated to give an oil. The oil is crystallized from acetone-hexanethen is recrystallized from the same solvent pair to give 20.88 g. of3-amino-4-methyl-1-phenyl-2-pyrazoline as colorless crystals, m.p.83°-84° C.

A mixture of 5.0 g. of the preceding compound and 25.0 ml. oftrifluoroacetic anhydride is allowed to stand for 2 minutes. The solidwhich separates is collected by filtration and washed with hexane. Thesolid is dissolved in dichloromethane. This solution is passed through ahydrous magnesium silicate and recrystallized as described in Example 2to give 1.82 g. of the desired product as needles, m.p. 142°-143.5° C.

EXAMPLE 72,2,2-Trifluoro-N-[4-methyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide

A mixture of 5.0 g. of 3-amino-4-methyl-1-phenyl-2-pyrazoline (preparedas described in Example 6) and 25.0 ml. of trifluoroacetic anhydride isallowed to stand at room temperature for 24 hours. Dichloromethane isadded to dissolve the solid formed then the solvent is evaporated. Thesolid is again dissolved in dichloromethane. This solution is columnizedand recrystallized as described in Example 2 to give 5.2 g. of theproduct of the Example as pale yellow needles, m.p. 203°-204° C.

EXAMPLE 82,2,2-Trifluoro-N-[1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide

A 2.0 g. amount of sodium metal is dissolved in 100 ml. of absoluteethanol, then 40.0 ml. of phenylhydrazine is added followed by 26.0 ml.of acrylonitrile. The reaction mixture is refluxed for 3 hours withexothermic crystallization of a product. The product is collected byfiltration and washed with 95% ethanol. The material is recrystallizedfrom dichloromethane-benzene to give 43.6 g. of3-amino-1-phenyl-2-pyrazoline as a solid, m.p. 168°-170.5° C.

A mixture of 1.5 g. of the preceding product and 8.0 ml. oftrifluoroacetic anhydride (exothermic reaction) is allowed to stand atroom temperature for one hour. The mixture is evaporated to dryness invacuo then dichloromethane is added. The solution is filtered and thefiltrate is evaporated to give 1.2 g. of the desired product as yellowneedles, m.p. 228.5°-230.5° C.

EXAMPLE 9 N-(1,5-Diphenyl-2-pyrazolin-3-yl)-2,2,2-trifluoroacetamide

A 5.0 g. amount of 3-amino-1,5-diphenyl-2-pyrazoline (prepared inExample 4) and 25.0 ml. of trifluoroacetic anhydride is heated untilsolution. After standing for 2 minutes, the precipitate formed iscollected by filtration and washed with hexane. The solid is dissolvedin dichloromethane and passed through a short column of a hydrousmagnesium silicate. The effluent is refluxed and hexane is added tocrystallize the product. The product is recrystallized from hexane togive 0.95 g. of the desired product as needles, m.p. 151.5°-153.5° C.

EXAMPLE 10N-[1-(m-Chlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

(A) A 1.0 g. amount of sodium metal is dissolved in 100 ml. of absoluteethanol, then 30.75 g. of m-chlorophenylhydrazine is added followed in 5minutes by 12.0 g. of acrylonitrile. The reaction mixture is refluxedfor 5 hours then is cooled and filtered. The solid collected isdissolved in acetone, treated with activated charcoal and filtered.Hexane is added to the filtrate to crystallize the product which iscollected to give 30.7 g. of 3-amino-1-(m-chlorophenyl)-2-pyrazoline asoff-white prisms, m.p. 131°-132° C.

(B) A 5.0 g. amount of the above product is added to 25.0 ml. oftrifluoroacetic anhydride giving an exothermic reaction with formationof a precipitate. After 5 minutes standing, the precipitate is collectedby filtration. The solid is dissolved in dichloromethane then is passedthrough a short column of a hydrous magnesium silicate. The effluent isrefluxed and hexane is added until turbidity results. Then the mixtureis cooled and filtered to provide 4.7 g. of the desired product asyellow crystals, m.p. 143°-144° C.

EXAMPLE 11N-[1,5-Bis(p-chlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

Sodium metal (2.8 g.) is dissolved in 125 ml. of absolute ethanol, then17.9 g. of p-chlorophenylhydrazine hydrochloride is added followed by16.36 g. of p-chlorocinnamonitrile. The reaction mixture is refluxed for7 hours and is allowed to stand at room temperature for 16 hours. Thesolvent is removed in vacuo and water is added to separate a solid. Thesolid is collected by filtration, dissolved in dichloromethane, and iscolumnized and crystallized as for Example 9. The product isrecrystallized from acetone-hexane to give 10.0 g. of3-amino-1,5-bis(p-chlorophenyl)-2-pyrazoline as colorless needles, m.p.150°-150.5° C.

A 5.0 g. amount of the preceding compound is mixed with 25.0 ml. oftrifluoroacetic anhydride at room temperature. The mixture is allowed tostand for 16 hours, then is filtered. The solid is dissolved indichloromethane. The solution is columnized and crystallized asdescribed above to give 4.52 g. of the desired product as light yellowmatted needles, m.p. 138.5°-140° C.

EXAMPLE 122-Bromo-N-[1-(α,α,α-trifluoro-m-tolyl)-2-pyrazolin-3-yl]propionamide

Sodium metal (2.8 g.) is dissolved in 125 ml. of absolute ethanol, then21.2 g. of m-trifluoromethylphenylhydrazine hydrochloride is addedfollowed by 5.5 g. of acrylonitrile. The reaction mixture is refluxedfor 18 hours. The solvent is removed in vacuo and water is added to theresidue to give a tacky solid. The solid is dissolved indichloromethane. The solution is dried over anhydrous magnesium sulfateand passed through a short column of a hydrous magnesium silicate. Theeffluent is collected and concentrated to separate tan crystals. Thismaterial is recrystallized from acetone-hexane to give 14.8 g. of3-amino-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazoline as pale yellow needles,m.p. 104°-105° C.

To 100 ml. of chloroform with stirring is added 2.75 g. of potassiumcarbonate and 5.3 g. of3-amino-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazoline, then 5.0 g. ofα-bromopropionylchloride is added dropwise. After the addition iscomplete the reaction mixture is refluxed on a steam bath for 4 hours.Then the solvent is removed in vacuo and water is added to give a gum.The gum is extracted with dichloromethane. The extracts are combined anddried over anhydrous magnesium sulfate. The solution is passed through ashort column of a hydrous magnesium silicate, then is evaporated leavinga gummy solid. The solid is triturated with ether to give 1.13 g. of ayellow solid. The solid is recrystallized from acetone-hexane to givethe desired product as yellow crystals, m.p. 54°-56° C.

EXAMPLE 132-Dimethylamino-N-[1-(α,α,α-trifluoro-m-tolyl)-2-pyrazolin-3-yl]propionamide

A 1.0 g. amount of2-bromo-N-[1-(α,α,α-trifluoro-m-tolyl)-2-pyrazolin-3-yl]propionamide(Example 12) is dissolved in 50 ml. of benzene in a pressure bottle,then 2.0 ml. of dimethylamine is added and the bottle is sealed for 1/2hour at room temperature with the separation of crystals. The mixture isheated on a steam bath for 6 hours, then is cooled. The reaction mixtureis partitioned between water and benzene. The benzene layer is driedover anhydrous magnesium sulfate and evaporated to a dark gum. The gumis dissolved in hexane and filtered through a hydrous magnesiumsilicate. The filtrate is evaporated to a gum (0.9 g.). A 210 mg. amountof this gum is chromatographed by thick layer chromatography on one mmSilica Gel G plates using the upper phase of a mixture of 2 partsbenzene, 1 part acetone and 2 parts water to give 180 mg. of the desiredproduct as a light yellow gum.

EXAMPLE 14N-[1-(3,4-Dichlorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

(A) A 2.8 g. amount of sodium metal is dissolved in 125 ml. of absoluteethanol, then 21.35 g. of 3,4-dichlorophenylhydrazine hydrochloride isadded followed in 5 minutes by 6.7 g. of crotononitrile. The reactionmixture is refluxed for 8 hours, then is evaporated to dryness in vacuo.Water is added to separate an oil. The oil is crystallized, then isdissolved in dichloromethane and is passed through a short column of ahydrous magnesium silicate. The effluent is refluxed with the gradualaddition of hexane to separate 14.4 g. of3-amino-1-(3,4-dichlorophenyl)-5-methyl-2-pyrazoline as colorlessprisms, m.p. 103°-104° C.

(B) A mixture of 2.5 g. of the above compound and 15.0 ml. oftrifluoroacetic anhydride is allowed to stand at room temperature forone hour. The reaction mixture is filtered to collect a solid. The solidis dissolved in dichloromethane. This solution is passed through a shortcolumn of a hydrous magnesium silicate. The effluent is heated on asteam bath and hexane is added to crystallize a product. The product iscollected, then the entire crystallization procedure is repeated to give2.50 g. of the product of the Example as needles, m.p. 150°-152° C.

EXAMPLE 15 N-[1-(3,4-Dichlorophenyl)-4-methyl-2-pyrazolin-3-yl]formamide

A 2.8 g. amount of sodium metal is dissolved in 200 ml. of absoluteethanol, then 21.35 g. of 3,4-dichlorophenylhydrazine hydrochloride isadded followed in 30 minutes by 6.7 g. of methacrylonitrile. Thereaction mixture is refluxed for 5 hours, then is evaporated to drynessin vacuo. Water is added to separate a solid. The solid is collected anddissolved in dichloromethane. This solution is passed through a shortcolumn of a hydrous magnesium silicate and recrystallized as describedin Example 2 to give 16.65 g. of3-amino-1-(3,4-dichlorophenyl)-4-methyl-2-pyrazoline as colorlessprisms, m.p. 131°-132.5° C.

A mixture of 3.0 g. of the preceding compound and 15 ml. of a mixture offormic acid and acetic anhydride (Feiser and Feiser, Reagents forOrganic Synthesis, Vol. 1, page 4) is allowed to stand at roomtemperature for 1/2 hour. The reaction mixture is poured onto ice thenis filtered to collect a solid. The solid is dissolved indichloromethane and treated as described in Example 2 to give 2.72 g. ofthe desired product as yellow prisms, m.p. 150°-152° C.

EXAMPLE 16 N-[1-(3,4-Dichlorophenyl)-2-pyrazolin-3-yl]formamide

A mixture of 5.0 g. of 3-amino-1-(3,4-dichlorophenyl)-2-pyrazoline(prepared in Example 1) and 25 ml. of a mixture of formic acid andacetic anhydride (Example 15) is allowed to stand at room temperaturefor one hour. The resulting solid is collected by filtration and washedwith hexane. The solid is dissolved in dichloromethane and is columnizedand recrystallized as described in Example 5 to give 3.85 g. of thedesired product as yellow prisms, m.p. 151°-153° C.

EXAMPLE 17N-[1-(4-Biphenylyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

A 5.0 g. amount of 4-amino-biphenyl is suspended in a stirred solutionof 40.0 ml. of concentrated hydrochloric acid and 27.0 ml. of watermaintained at 5° C. Stirring is continued and the temperature ismaintained below 10° C. during the slow addition of a solution of 8.0 g.of sodium nitrite in 16.0 ml. of water. The reaction mixture is stirredfor 15 minutes longer at 5° C. then is added slowly to a cooled solution(0°-5° C.) of 53.0 g. of stannous chloride in 53.0 ml. of concentratedhydrochloric acid. The resulting mixture is diluted with water andtreated with a 40% solution of sodium hydroxide until alkaline. Thesolid formed is collected by filtration, dissolved in dichloromethane,dried over anhydrous magnesium sulfate and filtered. The filtrate ispassed through a short column of a hydrous magnesium silicate. Theeffluent is evaporated in vacuo to give a solid. The solid is dissolvedin dichloromethane. This solution is heated to boiling and hexane isadded until trubidity occurs. The mixture is cooled and filtered to give8.5 g. of 4-biphenylhydrazine as orange crystals, m.p. 135°-138° C.(dec.).

A 4.3 g. amount of the preceding compound is added to a solution of 0.1g. of sodium metal dissolved in 100 ml. of absolute ethanol. Then 1.54g. of crotononitrile is added and the mixture is refluxed for 6 hoursand poured into water to separate a dark solid. The solid is dissolvedin dichloromethane, heated to reflux and recrystallized twice withhexane as previously described to give 3.6 g. of3-amino-1-(4-biphenylyl)-5-methyl-2-pyrazoline as a solid, m.p.174°-176° C.

A 0.5 g. amount of the preceding compound is dissolved in 2.5 ml. oftrifluoroacetic anhydride and allowed to remain at room temperature for2 hours. The solvent is removed in vacuo and water is added to separatea solid. The solid is collected, dissolved in dichloromethane and iscolumnized and recrystallized as in Example 2 to give the product of theExample as yellow crystals, m.p. 192°-193° C.

EXAMPLE 18 N-(1-Phenyl-2-pyrazolin-3-yl) acetamide

A 10.0 g. amount of 3-amino-1-phenyl-2-pyrazoline (prepared in Example8) and 10.0 ml. of acetic anhydride are mixed together and allowed tostand at room temperature for one hour. The resulting solid iscollected, dissolved in dichloromethane and passed through a shortcolumn of a hydrous magnesium silicate. The effluent is heated andhexane is added to crystallize 1.2 g. of the desired product as yellowprisms, m.p. 190°-191° C.

EXAMPLE 19 N-[1-(m-Chlorophenyl)-2-pyrazolin-3-yl]formamide

A mixture of 2.0 g. of 3-amino-1-(m-chlorophenyl)-2-pyrazoline (preparedin Example 10) and 10 ml. of a mixture of formic acid and aceticanhydride (Example 15) is allowed to stand at room temperature for 30minutes. Then the solvent is evaporated in vacuo to give an oil. The oilis dissolved in dichloromethane and is columnized and recrystallized asdescribed in Example 5 to give 1.32 g. of the desired product as paleyellow needles, m.p. 143°-145° C.

EXAMPLE 20 N-[1-(p-Chlorophenyl)-5-methyl-2-pyrazolin-3-yl]formamide

A 1.72 g. amount of sodium metal is dissolved in 10 ml. of absoluteethanol, then 11.0 g. of p-chlorophenylhydrazine hydrochloride is addedfollowed in 15 minutes by 4.20 g. of crotononitrile. The reactionmixture is refluxed for 18 hours. The solvent is removed in vacuo andwater is added to the residue to separate a gum. The gum is dissolved indichloromethane and separated from the aqueous layer. The organic layeris dried over anhydrous magnesium sulfate and filtered through a shortcolumn of a hydrous magnesium silicate. The effluent is evaporated togive a glass. A small amount of benzene and then hexane is added to theglass which gradually solidifies. The solid is collected, washed withhexane and dried to give 8.1 g. of3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline as a pink solid, m.p.90°-92° C.

A 4.8 g. amount of the above compound is dissolved in 25.0 ml. of amixture of formic acid and acetic anhydride (Example 15). The reactionmixture is allowed to remain at room temperature for 3 hours, then icewater is added to separate a gum. The aqueous phase is decanted and thegum is dissolved in dichloromethane. The solution is dried overmagnesium sulfate and passed through a hydrous magnesium silicate. Theeffluent is evaporated leaving a gum. The gum is dissolved indichloromethane. The solution is heated and hexane is added untilturbidity results. The mixture is cooled and filtered to yield 3.6 g. ofthe desired product as off-white crystals, m.p. 112°-113° C.

EXAMPLE 21N-[1-(p-Chlorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

An 8.0 g. amount of 3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline(prepared as described in Example 20) is dissolved in 25.0 ml. ofdichloromethane with stirring. This solution is slowly added withstirring to 25.0 ml. of trifluoroacetic anhydride cooled at 10° C. Thereaction mixture is stirred for 3 hours at room temperature, then thesolvent is removed in vacuo. The residue is dissolved in dichloromethaneand this solution is passed through a short column of a hydrousmagnesium silicate. The effluent is concentrated while adding hexaneuntil turbidity results. The solution is cooled, then filtered to give8.5 g. ofN-[1-(p-chlorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamideas a white solid, m.p. 170°-172° C.

EXAMPLE 22 N-(1-Phenyl-2-pyrazolin-3-yl)formamide

A mixture of 10.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared inExample 8) and 50.0 ml. of a mixture of formic acid and acetic anhydride(Example 15) is allowed to stand at room temperature for 3 hours. Wateris added and the white crystals are collected by filtration. The solidis dissolved in dichloromethane. The solution is dried over magnesiumsulfate and filtered through a hydrous magnesium silicate. The filtrateis evaporated in vacuo to give pink crystals. A 500 mg. portion of crudeproduct is recrystallized from dichloromethane-hexane to give 403 mg. ofthe desired product as a white solid, m.p. 140°-141° C.

EXAMPLE 23 N-[1-(p-Chlorophenyl)-4-methyl-2-pyrazolin-3-yl]formamide

A 1.2 g. amount of sodium metal is dissolved in 110 ml. of absoluteethanol, then 7.5 g. of p-chlorophenylhydrazine hydrochloride is addedfollowed by 2.9 g. of methacrylonitrile. The reaction mixture isrefluxed for 18 hours. The solvent is removed in vacuo and water isadded to the residue to separate a gum. The gum is collected anddissolved in dichloromethane. The organic solution is washed with water,dried over anhydrous magnesium sulfate and filtered through a shortcolumn of a hydrous magnesium silicate. The effluent is evaporatedleaving a gum which solidifies upon adding hexane. The solid iscollected and recrystallized from ether-hexane to give 4.6 g. of3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline as white crystals, m.p.107°-108° C.

A 2.2 g. amount of the preceding compound is dissolved in 10.0 ml. of amixture of formic acid and acetic anhydride (Example 15). The mixture isallowed to remain at room temperature for 3 hours. Water is added and ayellow solid is collected by filtration. The solid is dissolved indichloromethane. The solution is dried over anhydrous magnesium sulfateand filtered through a hydrous magnesium silicate. The filtrate isconcentrated while adding hexane until turbidity occurs. The mixture iscooled and filtered to give 2.1 g. of the product of the Example as awhite solid, m.p. 172°-174° C.

EXAMPLE 24 N-[1-(m-Chlorophenyl)-4-methyl-2-pyrazolin-3-yl]formamide

A 3.12 g. amount of sodium metal is dissolved in 200 ml. of absoluteethanol, then 20.9 g. of m-chlorophenylhydrazine hydrochloride is added,followed by 7.6 g. of methacrylonitrile. The reaction mixture isrefluxed for 18 hours. The solvent is removed in vacuo and water isadded to separate a solid. The solid is collected, dissolved indichloromethane, dried over anhydrous magnesium sulfate and filteredthrough a hydrous magnesium silicate. The filtrate is evaporated to givea solid. The solid is recrystallized twice from ether-hexane to give16.2 g. of 3-amino-1-(m-chlorophenyl)-4-methyl-2-pyrazoline as whitecrystals, m.p. 84°-85° C.

A 3.0 g. amount of the preceding product is dissolved in 10 ml. of amixture of formic acid and acetic anhydride (Example 15). The mixture isallowed to remain at room temperature for 3 hours, then is poured intoice water to separate a partial gum and solid. This material iscollected, dissolved in dichloromethane and filtered through a shortcolumn of a hydrous magnesium silicate. The effluent is concentratedwhile adding hexane to separate 3.1 g. of the product of the Example aslight yellow crystals, m.p. 140°-142° C.

EXAMPLE 25 N-(5-Methyl-1-phenyl-2-pyrazolin-3-yl)acetamide

A mixture of 2.0 g. of 3-amino-5-methyl-1-phenyl-2-pyrazoline (preparedin Example 5), 5.0 ml. of acetic anhydride and 100 mg. of4-dimethylaminopyridine is allowed to stand at room temperature for 3hours. The mixture is filtered to give a white solid. The solid isdissolved in dichloromethane and is columnized and recrystallized as forExample 14 (B) to give 0.90 g. of the desired product as colorlessplates, m.p. 144.5-146.5° C.

EXAMPLE 26 N-[1-(p-Fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

(A) Sodium metal (2.8 g.) is dissolved in 200 ml. of absolute ethanol,then 16.73 g. of p-fluorophenylhydrazine hydrochloride is added followedin 10 minutes by 6.7 g. of crotononitrile. The reaction mixture isrefluxed for 16 hours. The solvent is removed in vacuo and water isadded to the residue to separate a solid. The solid is dissolved indichloromethane. The solution is passed through a short column of ahydrous magnesium silicate. The effluent is refluxed and hexane is addedto crystallize 11.0 g. of3-amino-1-(p-fluorophenyl-5-methyl-2-pyrazoline as prisms, m.p.133°-135° C.

(B) A mixture of 3.0 g. of the preceding compound and 7.5 ml. of aceticanhydride is allowed to remain at room temperature for 16 hours. Themixture is filtered to collect a solid. The solid is dissolved indichloromethane. The solution is columnized and crystallized as forExample 14 (B) to give 1.3 g. of the product of the Example as colorlessneedles, m.p. 136.5°-137.5° C.

EXAMPLE 27N-[5-(p-Chlorophenyl)-1-(m-fluorophenyl)-2-pyrazolin-3-yl]acetamide

A 1.4 g. amount of sodium metal is dissolved in 150 ml. of absoluteethanol, then 8.1 g. of m-fluorophenylhydrazine hydrochloride is addedfollowed in 5 minutes by 8.18 g. of p-chlorocinnamonitrile. The reactionmixture is heated at reflux for 6 hours, then is filtered and cooled.The solvent is partially evaporated and water is added to separate asemi-solid which is collected, dissolved in dichloromethane and iscolumnized and crystallized twice as for Example 9 to give 2.4 g. of3-amino-5-(p-chlorophenyl)-1-(m-fluorophenyl)-2-pyrazoline as colorlessneedles, m.p. 135.5°-136° C.

A mixture of 2.5 g. of the above compound and 7.5 ml. of aceticanhydride is allowed to stand at room temperature for 16 hours. Theresulting clear dark solution is poured into a mixture of 50 ml. ofwater, 50 ml. of ethanol and 20 ml. of 5 N sodium hydroxide. Thereaction mixture is refluxed for 30 minutes on a steam bath, then iscooled and filtered to collect a solid. The solid is dissolved indichloromethane and is columnized and crystallized as for Example 10 (B)to give 1.82 g. of the desired product as yellow needles, m.p.182°-183.5° C.

EXAMPLE 28N-[5-(p-Chlorophenyl)-1-(p-fluorophenyl)-2-pyrazolin-3-yl]acetamide

A 2.8 g. amount of sodium metal is dissolved in 100 ml. of absoluteethanol, then 16.26 g. of p-fluorophenylhydrazine hydrochloride is addedfollowed in 5 minutes by 16.35 g. of p-chlorocinnamonitrile. Thereaction mixture is refluxed for 20 hours, then the solvent isevaporated in vacuo. Water is added to separate a solid. The solid isdissolved in dichloromethane and is columnized and crystallized as forExample 5 (A) to yield 8.95 g. of3-amino-5-(p-chlorophenyl)-1-(p-fluorophenyl)-2-pyrazoline as a palecoral colored solid, m.p. 182°-183° C.

A mixture of 4.0 g. of the preceding product and 15.0 ml. of aceticanhydride is allowed to stand at room temperature for 16 hours. Then themixture is poured into a mixture of 50 ml. of water, 50 ml. of 95%ethanol and 55 ml. of 5 N aqueous sodium hydroxide. The reaction mixtureis refluxed on a steam bath for 30 minutes, then is cooled and filteredto collect a solid. The solid is dissolved in dichloromethane and iscolumnized and crystallized as for Example 10 (B) to yield 2.3 g. of theproduct of the Example as off-white needles, m.p. 133°-135° C.

EXAMPLE 29 N-[1-(p-Chlorophenyl)-2-pyrazolin-3-yl]acetamide

Sodium metal (2.8 g.) is dissolved in 200 ml. of absolute ethanol, then17.9 g. of p-chlorophenylhydrazine hydrochloride is added followed in 25minutes by 5.5 g. of acrylonitrile. The reaction mixture is refluxed for6 hours, then is filtered hot. The filtrate is evaporated to dryness invacuo, then water is added to separate a solid. The solid is collectedby filtration, then is dissolved in dichloromethane and columnized andcrystallized as for Example 10 (B) to give 8.75 g. of3-amino-1-(p-chlorophenyl)-2-pyrazoline as colorless needles, m.p.142.5°-145° C.

A mixture of 0.5 g. of the preceding product and 1.25 ml. of aceticanhydride is allowed to remain at room temperature for 16 hours. Themixture is chilled and filtered to give 222 mg. of pale yellow crystals.The material is recrystallized from dichloromethane-hexane to give theproduct of the Example as a white solid, m.p. 168°-170° C.

EXAMPLE 30N-[1-(p-Chlorophenyl)-4-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

A 7.0 g. amount of 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline(prepared as described in Example 23) is dissolved in 25.0 ml. ofdichloromethane and cooled to 5° C. The solution is stirred and 14.0 ml.of trifluoroacetic anhydride is added. Stirring is continued at roomtemperature for 3 hours, then the solvent is removed in vacuo. Theresidue is dissolved in dichloromethane and the solution is concentratedwith the addition of hexane until turbidity appears. The mixture iscooled and the solid is collected to give 5.3 g. of product. A 1.0 g.amount of this material is recrystallized from dichloromethane-hexane togive 750 mg. of the desired product as a white solid, m.p. 181°-183° C.

EXAMPLE 31 N-[1-(p-Chlorophenyl)-4-methyl-2-pyrazolin-3-yl]acetamide

A 9.0 g. amount of 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline(prepared as described in Example 23) is dissolved in 54.0 ml. of aceticanhydride. The warm solution is allowed to stand for 16 hours at roomtemperature with some solid separation. The solid is collected byfiltration and is dissolved in methanol. Then 1 N potassium hydroxide inmethanol is added to make basic. After 15 minutes at room temperature,the solvent is removed in vacuo and water is added to separate a solid.The solid is collected and recrystallized from dichloromethane-hexane togive 6.5 g. of the desired product as white crystals, m.p. 172°-173° C.

EXAMPLE 32 N-[1-(p-Chlorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

A mixture of 8.0 g. of 3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline(prepared as described in Example 20), 400 mg. of4-dimethylaminopyridine and 20.0 ml. of acetic anhydride is allowed tostand at room temperature for 48 hours. The solid formed is collected byfiltration, washed with cold acetic anhydride, then with hexane and isdried to give a white solid. The solid is recrystallized fromdichloromethane-hexane to give 6.6 g. of the product of the Example as awhite solid, m.p. 167°-169° C.

EXAMPLE 33 N-(4-Methyl-1-phenyl-2-pyrazolin-3-yl)acetamide

A 10.0 g. amount of 3-amino-4-methyl-1-phenyl-2-pyrazoline (prepared asdescribed in Example 6) is dissolved in 50 ml. of acetic anhydride, then500 mg. of 4-dimethylaminopyridine is added and the reaction mixture isallowed to stand at room temperature for 18 hours. The mixture is pouredinto water to separate a gum which solidifies and is collected byfiltration. The solid is added with stirring to 150 ml. of methanolcontaining 10.0 g. of sodium hydroxide. After 30 minutes, the solvent isremoved in vacuo and water is added to provide a gum which becomessolid. This solid is dissolved in dichloromethane, dried over anhydrousmagnesium sulfate and passed through a short column of a hydrousmagnesium silicate. The effluent is concentrated while adding hexane toyield crystals. The material is collected and dried to give 3.3 g. ofthe desired product as a white solid, m.p. 149°-150° C.

EXAMPLE 34 N-[1-(p-Trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide

A mixture of 800 mg. of N-(1-phenyl-2-pyrazolin-3-yl)acetamide (Example18) and 5.0 ml. of trifluoroacetic anhydride is allowed to stand at roomtemperature for 30 minutes. Then the mixture is evaporated to dryness invacuo. The residue is dissolved in dichloromethane and is columnized andcrystallized as for Example 10 (B) to yield 85 mg. of the desiredproduct as yellow needles, m.p. 243°-244° C.

EXAMPLE 35 N-(1-Phenyl-2-pyrazolin-3-yl)propionamide

A mixture of 10.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared asdescribed in Example 8), 50 ml. of propionic anhydride and 200 mg. of4-dimethylaminopyridine is kept at room temperature for 30 minutes. Themixture is cooled and filtered to give yellow crystals. The solid isdissolved in dichloromethane and is columnized and crystallized as forExample 10 (B) to yield 4.55 g. of the product of the Example ascolorless crystals, m.p. 170.5°-171° C.

EXAMPLE 36 N-[1-(m-Fluorophenyl)-4-methyl-2-pyrazolin-3-yl]acetamide

A 2.8 g. amount of sodium metal is dissolved in 200 ml. of absoluteethanol, then 16.2 g. of m-fluorophenylhydrazine hydrochloride is added,followed by 13.4 g. of methacrylonitrile. The reaction mixture isrefluxed for 18 hours, then the solvent is evaporated in vacuo. Water isadded to give a gum. The gum is dissolved in dichloromethane and thesolution is passed through a short column of a hydrous magnesiumsilicate. The effluent is concentrated while adding hexane untilturbidity occurs. The solution is cooled and seeded to separate a pinksolid which is collected by filtration and dried to give 4.2 g. of3-amino-1-(m-fluorophenyl)-4-methyl-2-pyrazoline.

A 4.2 g. amount of the preceding compound is dissolved in 10.0 ml. ofacetic anhydride then 100 mg. of 4-dimethylaminopyridine is added andthe reaction mixture is allowed to stand at room temperature for 16hours. The mixture is poured into water to separate a gum whichsolidifies. The solid is collected by filtration and washed with water.The solid is dissolved in 50.0 ml. of methanol and 10.0 ml. of 1 Nsodium hydroxide in methanol is added. The mixture is allowed to standat room temperature for 30 minutes, then the solvent is partly removedin vacuo. The addition of water separates a yellow solid. The solid iscollected and dried to give 4.1 g. of the product of the Example, m.p.171°-172° C.

EXAMPLE 37 N-(1-m-Tolyl-2-pyrazolin-3-yl)acetamide

A 2.8 g. amount of sodium metal is dissolved in 100 ml. of absoluteethanol, then 15.8 g. of m-tolylhydrazine hydrochloride is addedfollowed in 5 minutes by 9.9 g. of β-ethoxypropionitrile. The reactionmixture is refluxed for 16 hours, then is evaporated to dryness invacuo. Water is added to the residue to separate a solid. The solid isdissolved in dichloromethane and is columnized and crystallized asdescribed in Example 26 (A) to give 10.1 g. of3-amino-1-m-tolyl-2-pyrazoline as colorless crystals, m.p. 119°-120° C.

A mixture of 3.0 g. of the above compound, 15.0 ml. of acetic anhydrideand 150 mg. of 4-dimethylaminopyridine is allowed to stand at roomtemperature for 16 hours. The mixture is filtered to collect a smallamount of solid. The solid is washed with hexane. The filtrate isallowed to stand for 16 hours and is filtered to collect additionalsolid. This material is washed with hexane. The solids are combined andagain washed with hexane to give 1.72 g. of the desired product asoff-white crystals, m.p. 222°-225° C.

EXAMPLE 38 2,2,2-Trifluoro-N-(1-phenyl-2-pyrazolin-3-yl)acetamide

A mixture of 5.0 g. of 3-amino-1-phenyl-2-pyrazoline (prepared asdescribed in Example 8), 200 ml. of dichloromethane, 5.0 ml. oftriethylamine and 7.0 ml. of trifluoroacetic anhydride is allowed toremain at room temperature for 30 minutes. The mixture is evaporated todryness in vacuo, then water is added to separate a semi-solid. Thesolid is dissolved in dichloromethane. The solution is dried overanhydrous sodium sulfate, columnized and recrystallized as for Example14 (B) to give 3.0 g. of the desired product as yellow-orange prisms,m,p. 163°-165° C.

EXAMPLE 392,2,2-Trifluoro-N-[4-methyl-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazolin-3-yl]acetamide

A 0.7 g. amount of sodium metal is dissolved in 35.0 ml. of absoluteethanol, then 5.3 g. of m-trifluoromethylphenylhydrazine hydrochlorideis added followed slowly by the addition of 1.7 g. of methacrylonitrile.The reaction mixture is refluxed for 18 hours. The solvent is removed invacuo and water is added to separate a solid. The solid is collected anddissolved in dichloromethane. The solution is dried over anhydrousmagnesium sulfate then is passed through a short column of a hydrousmagnesium silicate. The effluent is evaporated to give a solid. Thesolid is recrystallized from ether-hexane to give 3.6 g. of(±)-3-amino-4-methyl-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazoline as whitecrystals.

A 7.9 g. amount of the preceding compound (prepared as described above)is dissolved in 25.0 ml. of dichloromethane, then 15.8 ml. oftrifluoroacetic anhydride is added and the mixture is stirred at roomtemperature for 21/2 hours. The excess anhydride is removed in vacuo andthe reaction is repeated using hexane as the medium. The reactionmixture is again evaporated in vacuo and the resulting tan solid isdissolved in ether and is filtered through a 200 mesh syntheticmagnesium silicate adsorbent. The filtrate is concentrated while addinghexane to precipitate white crystals. The mixture is cooled for 16 hoursand filtered to yield 8.4 g. of the desired product, m.p. 121°-122° C.

EXAMPLE 40 N-(1,5-Diphenyl-2-pyrazolin-3-yl)formamide

A mixture of 5.0 g. of 3-amino-1,5-diphenyl-2-pyrazoline (prepared asdescribed in Example 4) and 25.0 ml. of a mixture of formic acid andacetic anhydride (Example 15) is allowed to remain at room temperaturefor 30 minutes. Then hexane is added and the mixture is filtered. Thesolid obtained is dissolved in dichloromethane. The solution iscolumnized and recrystallized as described in Example 14 (B) to yield3.55 g. of the product of the Example as off-white needles, m.p.158°-160° C.

EXAMPLE 412,2,2-Trifluoro-N-[1-(p-fluorophenyl)-2-pyrazolin-3-yl]acetamide

Sodium metal (2.8 g.) is dissolved in 100 ml. of absolute ethanol, then16.26 g. of p-fluorophenylhydrazine hydrochloride is added followed in 5minutes by 5.5 g. of acrylonitrile. The reaction mixture is refluxed for7 hours, then the solvent is evaporated near dryness and water is addedto separate a solid. The solid is dissolved in dichloromethane. Thesolution is columnized and the product is recrystallized as for Example5 (A) to give 6.6 g. of 3-amino-1-(p-fluorophenyl)-2-pyrazoline ascolorless needles, m.p. 114°-115° C.

A mixture of 4.15 g. of the preceding product, 100 ml. ofdichloromethane and 10.0 ml. of trifluoroacetic anhydride is allowed toremain at room temperature for 30 minutes. The mixture is evaporated todryness in vacuo. The resulting solid is washed with water, then isdissolved in dichloromethane. The solution is columnized and the desiredproduct is recrystallized as for Example 14 (A) to yield 5.45 g. as paleyellow prisms, m.p. 145.5°-147° C.

EXAMPLE 422,2,2-Trifluoro-N-[1-(4-trifluoroacetyl-m-tolyl)-2-pyrazolin-3-yl]acetamide

A mixture of 4.0 g. of 3-amino-1-m-tolyl-2-pyrazoline (prepared inExample 37) and 20.0 ml. of trifluoroacetic anhydride is stirred at roomtemperature giving an exothermic reaction resulting in a green solution.The solution is cooled to provide a precipitate. The solvent isevaporated in vacuo to give a solid. The solid is dissolved indichloromethane. The solution is columnized and the desired product isrecrystallized as described in Example 26 (A) to give 3.9 g. of theproduct of the Example as yellow needles, m.p. 171.5°-173° C.

EXAMPLE 432,2,2-Trifluoro-N-[1-(p-fluorophenyl)-5-phenyl-2-pyrazolin-3-yl]acetamide

Sodium metal (2.8 g.) is dissolved in 100 ml. of absolute ethanol, then16.2 g. of p-fluorophenylhydrazine hydrochloride is added followed in 5minutes by 12.9 g. of cinnamonitrile. The reaction mixture is refluxedfor 5 hours. Then the solvent is evaporated in vacuo. Water is added toseparate a solid. The solid is dissolved in dichloromethane and iscolumnized and recrystallized 3 times as described in Example 26 (A) togive 6.2 g. of 3-amino-1-(p-fluorophenyl)-5-phenyl-2-pyrazoline as buffcolored needles, m.p. 160°-161° C.

A mixture of 4.0 g. of the preceding compound, 50 ml. of dichloromethaneand 10 ml. of trifluoroacetic anhydride is allowed to remain at roomtemperature for 30 minutes. The solvent is evaporated in vacuo. Theresidual solid is washed with water and dried. The solid is dissolved indichloromethane. The solution is columnized and the desired product isrecrystallized as described in Example 26 (A) to give 4.36 g. ascolorless matted needles, m.p. 143°-143.5° C.

EXAMPLE 442,2,2-Trifluoro-N-[1-(p-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide

An 8.4 g. amount of sodium metal is dissolved in 420 ml. of absoluteethanol, then 48.8 g. of p-fluorophenylhydrazine hydrochloride is added,followed in 5 minutes by 20.1 g. of crotononitrile. The reaction mixtureis refluxed for 16 hours. The solvent is removed in vacuo and water isadded to separate a solid. The solid is collected by filtration anddissolved in dichloromethane. The solution is columnized and a productis recrystallized as for Example 26 (A) to give 25.5 g. of3-amino-1-(p-fluorophenyl)-5-methyl-2-pyrazoline as prisms, m.p.135°-136° C.

A mixture of 10.0 g. of the preceding product, 50 ml. of dichloromethaneand 25 ml. of trifluoroacetic anhydride is allowed to remain at roomtemperature for 30 minutes. The solvent is removed in vacuo and water isadded to separate a solid. The solid is collected and washed with asaturated sodium bicarbonate solution. The solid is dissolved indichloromethane. The solution is columnized and recrystallized twice asdescribed in Example 26 (A) to give 11.15 g. of the product of theExample as yellow crystals, m.p. 116°-117° C.

EXAMPLE 45 N-[1-(p-Fluorophenyl)-5-methyl-2-pyrazolin-3-yl]propionamide

A mixture of 3.0 g. of 3-amino-1-(p-fluorophenyl)-5-methyl-2-pyrazoline(prepared in Example 44) and 5.0 ml. of propionic anhydride is allowedto remain at room temperature for 2 hours. The reaction mixture ispoured into water and the water is decanted. This step is repeated. Theprecipitate is treated with saturated sodium bicarbonate solution thenis filtered. The solid is dissolved in dichloromethane. The solution iscolumnized and the desired product is recrystallized as described inExample 26 (A) to give 2.77 g. as colorless plates, m.p. 125°-126.5° C.

EXAMPLE 46 N-[1-(p-Fluorophenyl)-4-methyl-2-pyrazolin-3-yl]formamide

A 2.8 g. amount of sodium metal is dissolved in 150 ml. of absoluteethanol, then 16.26 g. of p-fluorophenylhydrazine hydrochloride is addedfollowed in 5 minutes by 6.7 g. of methacrylonitrile. The reactionmixture is refluxed for 8 hours, then the solvent is removed in vacuo.Water is added to the residue to separate an oil. The oil crystallizeson standing for 16 hours. The solid is dissolved in dichloromethane andis columnized and recrystallized twice as described in Example 26 (A) togive 8.65 g. of 3-amino-1-(p-fluorophenyl)-4-methyl-2-pyrazoline ascolorless prisms.

A mixture of 3.3 g. of the above compound and 15.0 ml. of a mixture offormic acid and acetic anhydride (Example 15) is allowed to remain atroom temperature for 16 hours. Water is added and the mixture isfiltered. The solid collected is recrystallized from acetone-hexane togive 2.65 g. of the desired product as pale yellow prisms, m.p.166°-168.5° C.

EXAMPLE 47 N-(5-Methyl-1-phenyl-2-pyrazolin-3-yl)propionamide

A mixture of 5.0 g. of 3-amino-5-methyl-1-phenyl-2-pyrazoline (preparedin Example 5) and 25.0 ml. of propionic anhydride is allowed to remainat room temperature for 16 hours. The reaction mixture is poured intowater to separate an oil which crystallizes. The solid is collected byfiltration and dissolved in dichloromethane. The solution is passedthrough a short column of a hydrous magnesium silicate. The effluent isheated at reflux and hexane is added. The first heavy precipitate(purple color) is discarded. The solution is cooled and the ensuingprecipitate is collected by filtration. The solid is again dissolved indichloromethane, columnized and recrystallized with hexane to give 2.3g. of the product of the Example as plates, m.p. 96.0°-96.5° C.

EXAMPLE 48 N-[1-(p-Fluorophenyl)-5-phenyl-2-pyrazolin-3-yl]formamide

A mixture of 5.0 g. of 3-amino-1-(p-fluorophenyl)-5-phenyl-2-pyrazoline(prepared as described in Example 43) and 85.0 ml. of a mixture offormic acid and acetic anhydride (Example 15) is allowed to remain atroom temperature for 2 hours. The solvent is evaporated in vacuo to givean oil. Water is added to separate a solid. The solid is dissolved indichloromethane and is columnized and recrystallized twice as describedin Example 26 (A) to give 3.55 g. of the desired product as colorlesscrystals, m.p. 158.5°-160.5° C.

EXAMPLE 49N-[5-(p-Chlorophenyl)-1-(m-fluorophenyl)-2-pyrazolin-3-yl]formamide

(A) Sodium metal (1.4 g.) is dissolved in 150 ml. of absolute ethanol.The solution is cooled in a cold water bath, then 8.1 g. ofm-fluorophenylhydrazine hydrochloride is added followed in 5 minutes by8.18 g. of p-chlorocinnamonitrile. The reaction mixture is heated atreflux for 6 hours then is filtered. The filtrate is cooled and water isadded. The semi-solid is collected by filtration, dissolved indichloromethane and is columnized and recrystallized twice as describedin Example 26 (A) to give 2.4 g. of3-amino-5-(p-chlorophenyl)-1-(m-fluorophenyl)-2-pyrazoline as colorlessneedles, m.p. 135.5°-136° C.

(B) A mixture of 2.0 g. of the preceding compound and 10.0 ml. of amixture of formic acid and acetic anhydride (Example 15) is allowed toremain at room temperature for 2 hours. The mixture is poured into waterto separate an oil which becomes semi-solid. The material is decanted,then water is added and the solid is collected by filtration. The solidis dissolved in dichloromethane and is columnized and recrystallized asdescribed in Example 26 (A) to yeild 1.02 g. of the desired product asoff-white needles, m.p. 128.5°-130.5° C.

EXAMPLE 50 N-[5-(p-Chlorophenyl)-1-phenyl-2-pyrazolin-3-yl]formamide

A mixture of 500 ml. of absolute ethanol, 5.0 ml. of 50% choline inmethanol, 32.4 g. of phenylhydrazine and 49.08 g. ofp-chlorocinnamonitrile is refluxed for 7 hours, then is allowed to standat room temperature for 16 hours. The solvent is evaporated in vacuo.The solid is dissolved in dichloromethane and the solution is columnizedand recrystallized twice as described in Example 26 (A) to give 12.0 g.of 3-amino-5-(p-chlorophenyl)-1-phenyl-2-pyrazoline as colorlessneedles, m.p. 183.5°-185.5° C.

A mixture of 10.0 g. of the preceding product and 100 ml. of a mixtureof formic acid and acetic anhydride (Example 15) is allowed to remain atroom temperature for 2.5 hours. The mixture is poured into water toseparate a semi-solid. The procedure of Example 49 (B) is followed toyield 6.3 g. of the desired product as yellow prisms, m.p. 135°-136° C.;resolidifies, then melts, m.p. 149°-150° C.

EXAMPLE 51 N-[1-(p-Chlorophenyl)-5-phenyl-2-pyrazolin-3-yl]formamide

A 5.52 g. amount of sodium metal is dissolved in 300 ml. of absolutemethanol. The solution is cooled in a cold water bath, then 35.8 g. ofp-chlorophenylhydrazine hydrochloride is added followed in 5 minutes by25.9 g. of cinnamonitrile. After 2 hours, the mixture is cooled to givea precipitate. Water is added and the mixture is extracted withdichloromethane. The organic layer is dried, then is columnized andrecrystallized as described in Example 26 (A) to give 22.5 g. of crudeproduct. A 5.0 g. amount of this material is recrystallized as above togive 3.35 g. of 3-amino-1-(p-chlorophenyl)-5-phenyl-2-pyrazoline ascolorless needles, m.p. 159°-161° C.

A mixture of 15.0 g. of the above crude product and 85.0 ml. of amixture of formic acid and acetic anhydride (Example 15) is allowed toremain at room temperature for 2 hours. The reaction mixture is pouredinto water and filtered to collect the solid. The solid is wahsed with asolution of saturated sodium bicarbonate, then water. The material isdried, dissolved in dichloromethane, then is columnized andrecrystallized as above to give 12.0 g. of the desired product as paleyellow crystals. A 5.0 g. amount of this material is recrystallized asabove to give 4.70 g. of the desired product, m.p. 164°-166° C.

EXAMPLE 52 N-(1,5-Diphenyl-2-pyrazolin-3-yl)propionamide

A mixture of 10.0 g. of 3-amino-1,5-diphenyl-2-pyrazoline (prepared inExample 4), 30.0 ml. of propionic anhydride and 500 mg. of4-dimethylaminopyridine is heated on a steam bath for 3 hours. Themixture is poured into water to separate an oil. The oil crystallizesand the solid is collected by filtration. The solid is dissolved indichloromethane. The solution is dried over anhydrous sodium sulfatethen is columnized and recrystallized twice as for Example 26 (A) togive 6.0 g. of the product of the Example as colorless plates, m.p.148.0°-148.5° C.

EXAMPLE 53N-[1-(p-Chlorophenyl)-5-phenyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide

A mixture of 2.75 g. of 3-amino-1-(p-chlorophenyl)-5-phenyl-2-pyrazoline(prepared in Example 51) and 10.0 ml. of trifluoroacetic anhydride isallowed to remain at room temperature for 16 hours. The solvent isevaporated in vacuo and the residue is dissolved in dichloromethane. Thesolution is columnized and recrystallized as for Example 26 (A) to give2.35 g. of the desired product as pale yellow crystals, m.p. 176°-178°C.

EXAMPLE 54 N-(1-Phenyl-5-p-tolyl-2-pyrazolin-3-yl)propionamide

A mixture of 4.5 g. of 3-amino-1-phenyl-5-p-tolyl-2-pyrazoline (preparedin Example 3), 20.0 ml. of propionic anhydride and 200 mg. of4-dimethylaminopyridine is heated on a steam bath for 2 hours. Thereaction mixture is cooled to room temperature then water is added toseparate a solid. The solid is collected then is dissolved indichloromethane. The solution is passed through a short column of ahydrous magnesium silicate. The effluent is heated at reflux and hexaneis added until turbidity appears. The mixture is cooled and filtered tocollect a solid. The solid is recrystallized again from 80% ethanol.This material is dissolved in 100 ml. of methanol, then 200 mg. ofpotassium carbonate is added and the mixture is refluxed for 15 minutes.Water is added until turbidity appears. The mixture is cooled andfiltered to collect the solid. The solid is dissolved indichloromethane. This solution is columnized and recrystallized asdescribed above to yield 2.4 g. of the desired product as colorlessneedles, m.p. 123.5° -125° C.

EXAMPLE 55 N-[1,5-Bis(p-chlorophenyl)-2-pyrazolin-3-yl]formamide

A 0.86 g. amount of sodium metal is dissolved in 100 ml. of absoluteethanol, then 7.0 g. of p-chlorophenylhydrazine hydrochloride is addedfollowed in 30 minutes by 5.5 g. of p-chlorocinnamonitrile. The reactionmixture is refluxed for 16 hours then the solvent is removed in vacuo.Water is added to separate a solid. The solid is collected and dissolvedin dichloromethane. The solution is passed through a short column of ahydrous magnesium silicate. The effluent is heated and hexane is added.The first oily material coming out of solution is removed by filtration.The filtrate is cooled to give a precipitate which is collected anddissolved in acetone. The solution is treated with activated charcoaland filtered. Hexane is added to the filtrate to crystallize a product.This material is recrystallized from acetone-hexane to give 1.48 g. of3-amino-1,5-bis(p-chlorophenyl)-2-pyrazoline as colorless needles, m.p.149°-150° C.

A mixture of 1.85 g. of 3-amino-1,5-bis(p-chlorophenyl)-2-pyrazoline(prepared as described above) and 10.0 ml. of a mixture of formic acidand acetic anhydride (Example 15) is allowed to remain at roomtemperature for 2 hours, then water is added and the mixture is filteredto collect a semi-solid. The solid is dissolved in dichloromethane andthe solution is columnized and recrystallized twice as for Example 26(A) to yield 1.10 g. of the product of the Example as off-whitecrystals, m.p. 198°-200° C.

EXAMPLE 56 Preparation of Compressed Tablet

    ______________________________________                                        Ingredient          mg./tablet                                                ______________________________________                                        Active Compound     0.5-500                                                   Dibasic Calcium Phosphate N.F.                                                                    qs                                                        Starch USP          40                                                        Modified Starch     10                                                        Magnesium Stearate USP                                                                            0.1-5.0 (% w/w)                                           ______________________________________                                    

EXAMPLE 57 Preparation of Compressed Tablet

    ______________________________________                                        Ingredient          mg./tablet                                                ______________________________________                                        Active Compound     0.5-500                                                   Dibasic Calcium Phosphate N.F.                                                                    qs                                                        Starch USP          40                                                        Modified Starch     10                                                        *Surfactant, e.g.                                                             Sodium Lauryl Sulfate                                                                             0.1-2.0 (% w/w)                                           Magnesium Stearate USP                                                                            0.1-5.0 (% w/w)                                           ______________________________________                                         *Other surface active agents such as disodium sulfosuccinate and nonionic     surface active agents such as Span® and Tween® may also be            employed.                                                                

EXAMPLE 58 Preparation of Compressed Tablet

    ______________________________________                                        Ingredient         mg./tablet                                                 ______________________________________                                        Active Compound    0.5-500                                                    Direct Compression Sugar                                                      Agent e.g. Emdex   qs                                                         Magnesium Stearate 0.1-3.0 (% w/w)                                            ______________________________________                                    

EXAMPLE 59 Preparation of Hard Shell Capsule

    ______________________________________                                        Ingredient       mg./capsule                                                  ______________________________________                                        Active Compound  0.5-500                                                      Lactose, Spray Dried                                                                           qs                                                           Magnesium Stearate                                                                             0.1-3.0 (% w/w)                                              ______________________________________                                    

EXAMPLE 60 Preparation of Oral Liquid (Syrup)

    ______________________________________                                        Ingredient        % w/v                                                       ______________________________________                                        Active Compound   0.05-5                                                      Liquid Sugar      75.0                                                        Methyl Paraben USP                                                                              0.18                                                        Propyl Paraben USP                                                                              0.02                                                        Suspending Agent                                                              e.g. Avicel       0.5-1.0                                                     Flavoring Agent   qs                                                          Purified Water qs ad                                                                            100.0                                                       ______________________________________                                    

EXAMPLE 61 Preparation of Oral Liquid (Elixir)

    ______________________________________                                        Ingredient        % w/v                                                       ______________________________________                                        Active Compound   0.05-5%                                                     Alcohol USP       12.5                                                        Glycerin USP      45.0                                                        Syrup USP         20.0                                                        Flavoring Agent   qs                                                          Purified Water qs ad                                                                            100.0                                                       ______________________________________                                    

EXAMPLE 62 Preparation of Oral Suspension (Syrup)

    ______________________________________                                        Ingredient        % w/v                                                       ______________________________________                                        Active Compound   0.05-5                                                      Polysorbate 80 USP                                                                              0.1                                                         Magnesium Aluminum                                                            Silicate, Colloidal                                                                             0.3                                                         Dye               0.001-0.5                                                   Flavoring Agent   qs                                                          Methyl Paraben USP                                                                               0.18                                                       Propyl Paraben USP                                                                               0.02                                                       Liquid Sugar      75.0                                                        Purified Water qs ad                                                                            100.0                                                       ______________________________________                                    

EXAMPLE 63 Preparation of Injectable Solution

    ______________________________________                                        Ingredient        % w/v                                                       ______________________________________                                        Active Compound   0.05-5                                                      Benzyl Alcohol N.F.                                                                             0.9                                                         Water for Injection                                                                             100.0                                                       ______________________________________                                    

EXAMPLE 64 Preparation of Injectable Oil

    ______________________________________                                        Ingredient       % w/v                                                        ______________________________________                                        Active Compound  0.05-5                                                       Benzyl Alcohol   1.5                                                          Sesame Oil qs ad 100.0                                                        ______________________________________                                    

EXAMPLE 65 Preparation of Intra-articular Product

    ______________________________________                                        Ingredient           Amount                                                   ______________________________________                                        Active Compound      2-20 mg.                                                 NaCl (physiological saline)                                                                        0.9%                                                     Benzyl Alcohol       0.9%                                                     Sodium Carboxymethylcellulose                                                 pH adjusted to 5.0-7.5                                                                             1-5%                                                     Water for Injection qs ad                                                                          100%                                                     ______________________________________                                    

EXAMPLE 66 Preparation of Injectable Depo Suspension

    ______________________________________                                        Ingredient         % w/v                                                      ______________________________________                                        Active Compound    0.05-5                                                                        (acid equivalent)                                          Polysorbate 80 USP 0.2                                                        Polyethylene Glycol 4000 USP                                                                     3.0                                                        Sodium Chloride USP                                                                              0.8                                                        Benzyl Alcohol N.F.                                                                              0.9                                                        HCl to pH 6-8      qs                                                         Water for Injection qs ad                                                                        100.0                                                      ______________________________________                                    

EXAMPLE 67 Preparation of Topical Cream

    ______________________________________                                        Ingredient         % w/w                                                      ______________________________________                                        Active Compound    0.05-5                                                     Sodium Lauryl Sulfate                                                                            1                                                          Propylene Glycol   12                                                         Stearyl Alcohol    25                                                         Petrolatum, White USP                                                                            25                                                         Methyl Paraben USP 0.18                                                       Propyl Paraben USP 0.02                                                       Purified Water qs  100                                                        ______________________________________                                    

EXAMPLE 68 Preparation of Topical Ointment

    ______________________________________                                        Ingredient         % w/w                                                      ______________________________________                                        Active Compound    0.05-5                                                     Cholesterol        3                                                          Stearyl Alcohol    3                                                          White Wax          8                                                          Petrolatum, White USP qs                                                                         100                                                        ______________________________________                                    

We claim:
 1. A compound selected from the group consisting of those ofthe formula: ##STR7## wherein R₁ is hydrogen or lower alkyl (C₁ -C₄); R₂is hydrogen, lower alkyl (C₁ -C₄), phenyl or ##STR8## where R₅ ishalogen; R₃ is ##STR9## where R₆ and R₇ are the same or different andmay be hydrogen, chloro, fluoro, lower alkyl (C₁ -C₄), trifluoromethylor COCF₃ ; R₄ is --COCF₃ ; and the pharmacologically acceptableacid-addition salts thereof.
 2. The compound according to claim 1,N-[1-(3,4-dichlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide. 3.The compound according to claim 1,2,2,2-trifluoro-N-[5-methyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide.4. The compound according to claim 1,2,2,2-trifluoro-N-[4-methyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide.5. The compound according to claim 1,N-(1,5-diphenyl-2-pyrazolin-3-yl)-2,2,2-trifluoroacetamide.
 6. Thecompound according to claim 1,N-[1-(m-chlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide.
 7. Thecompound according to claim 1,N-[1,5-bis(p-chlorophenyl)-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide.8. The compound according to claim 1,N-[1-(3,4-dichlorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide.9. The compound according to claim 1,N-[1-(p-chlorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2-trifluoroacetamide.10. The compound according to claim 1,2,2,2-trifluoro-N-(1-phenyl-2-pyrazolin-3-yl)acetamide.
 11. The compoundaccording to claim 1,2,2,2-trifluoro-N-[4-methyl-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazolin-3-yl]acetamide.12. The compound according to claim 1,2,2,2-trifluoro-N-[1-(p-fluorophenyl)-2pyrazolin-3-yl]acetamide.
 13. Thecompound according to claim 1,2,2,2-trifluoro-N-[1-(4-trifluoroacetyl-m-tolyl)-2-pyrazolin-3-yl]acetamide.14. The compound according to claim 1,2,2,2-trifluoro-N-[1-(p-fluorophenyl)-5-phenyl-2-pyrazolin-3-yl]acetamide.15. The compound according to claim 1,2,2,2-trifluoro-N-[1-(p-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide.